Transgenic mouse models for Alzheimer's disease (AD) offer the best hope for understanding and developing effective means of treating this dreadful disease. A number of laboratories, including ours, are working to develop useful models for this polygenic disease. Familial AD is often associated with mutations in the amyloid precursor protein (APP); one of the mutations is found in a Swedish population (APPSWED). Several groups have developed transgenic mice carrying the APPSWED gene but to date the most successful model is one developed by Hsaio/Ashe et al. (1995) called Tg2576. The proposed work is to cross the Tg2576 mice with mice generated in our laboratory that carry two common alleles for human apolipoprotein E (APOE), APOE-2 and APOE-4. APOE-4 is a risk factor for AD, and APOE-2 is reported to be beneficial in somehow retarding the development of AD. The ultimate goal is to obtain two mouse lines that each carry three transgenes; one carrying APOE-4, APPSWED, and mouse APOE-knockout (E-KO); the other carrying APOE-2, APPSWED, and E-KO. In addition, we also plan to similarly use a new APPSWED transgenic line recently developed in our laboratory to cross with APOE-2 and APOE-4 mouse lines. The new APPSWED line may be needed to elucidate any defects that may be due to mouse background strain. Once the proper crosses are obtained, the mice will be tested for (1) memory deficits and the age at which any deficits occur, (2) presence in brain of amyloidosis and content of b-amyloid peptide which is derived from APP and strongly implicated in the pathogenesis of AD, and (3) the presence of cerebral angiopathy which is found in AD. After demonstration of neuropathology in the mice, the effects of both diet restriction and high cholesterol diets will be tested to determine if the course of the pathology can be altered.